Abstract
Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / immunology*
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Antigens, CD / metabolism
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B7-1 Antigen / immunology*
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B7-1 Antigen / metabolism
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B7-2 Antigen / immunology*
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B7-2 Antigen / metabolism
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CD28 Antigens / immunology*
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CHO Cells
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CTLA-4 Antigen
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Cricetinae
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Cricetulus
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Dendritic Cells / immunology
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Endocytosis*
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Humans
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Jurkat Cells
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Ligands
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Lymphocyte Activation
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Mice
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Mice, Transgenic
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Models, Biological
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Ovalbumin / immunology
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Receptors, Antigen, T-Cell / immunology
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Recombinant Fusion Proteins / metabolism
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
Substances
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Antigens, CD
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B7-1 Antigen
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B7-2 Antigen
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CD28 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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Ligands
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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Ovalbumin